Bitter orange (Citrus aurantium) extract and its primary protoalkaloid p-synephrine are used widely in weight loss/weight management and sports performance products. Because of structural similarities, the pharmacological effects of p-synephrine are widely assumed to be similar to those of ephedrine, m-synephrine (phenylephrine), and endogenous amine neurotransmitters as norepinephrine and epinephrine. However, small structural changes result in the receptor binding characteristics of these amines that are markedly different, providing a plausible explanation for the paucity of adverse effects associated with the wide-spread consumption of p-synephrine in the form of dietary supplements as well as in various Citrus foods and juices. This paper summarizes the adrenoreceptor binding characteristics of p-synephrine relative to m-synephrine, norepinephrine, and other amines as related to the observed pharmacological effects. 1. Introduction p-synephrine (Figure 1) is the primary protoalkaloid in Citrus aurantium (bitter orange) and other Citrus species [1–14]. Bitter orange extract and p-synephrine are widely used in weight management and sports performance products. In addition to its consumption in dietary supplements, p-synephrine is daily consumed in various foods and juices derived from Citrus species as Seville oranges, mandarin oranges, clementines, Marrs sweet oranges, Nova tangerines, grapefruits and other orange-related species containing p-synephrine [12–15]. In spite of the wide-spread consumption and the lack of directly attributable adverse effects to p-synephrine and bitter orange extract [16–18], the safety of p-synephrine is frequently questioned. Various articles refer to the potential cardiovascular hazards that may occur as the result of using dietary supplements containing p-synephrine and bitter orange extract [19–24], with reference being made to clinical case reports that involve multiherbal and polyalkaloidal and poly-protoalkaloidal products [16, 17]. Figure 1: p-Synephrine. Current confusion regarding the safety of bitter orange extract and p-synephrine is clouded by multiple issues, including the use of complex mixtures of ingredients in products that include bitter orange extract, the existence of some structural similarities with ephedrine (Figure 2), the misunderstandings regarding the isomeric forms of synephrine and their differing pharmacological properties [18], and the release of misleading information by governmental agencies [25]. The projected warnings regarding cardiovascular risks are extrapolated from studies
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